Brain Advance Access originally published online on June 23, 2005
Brain 2005 128(8):1747-1763; doi:10.1093/brain/awh578
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Review Article |
Autoreactive CD8+ T cells in multiple sclerosis: a new target for therapy?
MRC Human Immunology Unit and Department of Clinical Neurology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK
Correspondence to: Lars Fugger, MD, PhD, MRC Human Immunology Unit and Department of Clinical Neurology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK E-mail: lars.fugger{at}imm.ox.ac.uk
Multiple sclerosis afflicts more than 1 million individuals worldwide and is widely considered to be an autoimmune disease. Traditionally, CD4+ T helper cells have almost exclusively been held responsible for its immunopathogenesis, partly because certain MHC class II alleles clearly predispose for developing multiple sclerosis and also, because of their importance in inducing experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis. However, several strategies that target CD4+ T cells beneficially in EAE have failed to ameliorate disease activity in multiple sclerosis, and some have even triggered exacerbations. Recently, the potential importance of CD8+ T cells has begun to emerge. Physiologically, CD8+ T cells are essential for detecting and eliminating abnormal cells, whether infected or neoplastic. In multiple sclerosis, genetic associations with MHC class I alleles have now been established, and CD8+ as well as CD4+ T cells have been found to invade and clonally expand in inflammatory central nervous system plaques. Recent animal models induced by CD8+ T cells show interesting similarities to multiple sclerosis, in particular, in lesion distribution (more inflammation in the brain relative to the spinal cord), although not all of the features of the human disease are recapitulated. Here we outline the arguments for a possible role for CD8+ T cells, a lymphocyte subset that has long been underrated in multiple sclerosis and should now be considered in new therapeutic approaches.
Key Words: multiple sclerosis; experimental autoimmune encephalomyelitis; T cells; CD8; autoimmunity
Abbreviations:
APC = antigen-presenting cells; ß2m = ß-2-microglobulin; CNS = central nervous system; CSF = cerebrospinal fluid; DC = dendritic cell; EAE = experimental autoimmune encephalomyelitis; EBV = Epstein–Barr virus; GA = glatiramer acetate; HLA = human leukocyte antigen; IFN-
= interferon-; IL = interleukin; LN = lymph node; MBP = myelin basic protein; MAG = myelin associated glycoprotein; MHC = major histocompatibility complex; MOG = myelin oligodendrocyte glycoprotein; MRI = magnetic resonance image(s); PLP = proteolipid protein; PPMS = primary progressive multiple sclerosis; RRMS = relapsing–remitting multiple sclerosis; SPMS = secondary progressive multiple sclerosis; TCR = T cell receptor; TH = CD4+ T helper cell; TNF-
= tumour necrosis factor-
Received March 24, 2005. Revised May 23, 2005. Accepted May 23, 2005.
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